Efficient new process for synthesis of 2-amino-5-chloro-n-,3-dimethylbenzamide

ABSTRACT

Described herein are novel methods of synthesizing 2-amino-5-chloro-N,3-dimethylbenzamide. Compounds prepared by the methods disclosed herein are useful for preparation of certain anthranilamide compounds that are of interest as insecticides, such as, for example, the insecticides chlorantraniliprole and cyantraniliprole.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a U.S. Divisional application of U.S. patentapplication Ser. No. 17/721,781, filed Apr. 15, 2022, which is a bypassU.S. Continuation application of International Patent Application No.PCT/US2020/057726, filed Oct. 28, 2020, which claims priority to U.S.Provisional Application No. 62/929,138, filed Nov. 1, 2019, each ofwhich is hereby incorporated by reference herein.

FIELD OF INVENTION

This disclosure is directed to novel methods of synthesizing2-amino-5-chloro-N,3-dimethylbenzamide. Compounds prepared by themethods disclosed herein are useful for preparation of certainanthranilamide compounds that are of interest as insecticides, such as,for example, the insecticides chlorantraniliprole and cyantraniliprole.

BACKGROUND

Conventional processes for the production of2-amino-5-chloro-N,3-dimethylbenzamide are subject to several industrialconcerns, such as hazardous materials, high cost, relatively long methodsteps, and complicated operations.

The present disclosure provides novel methods useful for preparing2-amino-5-chloro-N,3-dimethylbenzamide and derivatives thereof. Thebenefits of the methods of the present disclosure compared to previousmethods are numerous and include reduced cost, eliminated need for mixedsolvent separations, reduced waste, relatively short method steps,simplified operation complexity, and reduced process hazards.

BRIEF DESCRIPTION

In one aspect, provided herein is a method of preparing a compound ofFormula VI, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen,halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl;wherein at least one of R₇-R₁₀ is a halogen; andwherein R₁₁ is selected from branched C₁-C₁₀ alkyl and unbranched C₁-C₁₀alkyl, the method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula V, wherein

-   -   -   each of R₇-R₁₀ is independently selected from hydrogen,            halogen, halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl;        -   wherein at least one of R₇-R₁₀ is a halogen; and        -   wherein the compound of Formula V is prepared according to a            method comprising            -   i) forming a first mixture comprising                -   a) a compound of Formula III, wherein

-   -   -   -   -   each of R₁-R₄ is independently selected from                    hydrogen, halogen, and C₁-C₅ alkyl;                -   b) a solvent; and                -   c) a halogenation reagent;

            -   ii) reacting the first mixture;

            -   iii) introducing a second mixture to the first mixture                to form a third mixture, the second mixture comprising                -   d) an oxidation agent; and                -   e) a catalyst; and

            -   iv) reacting the third mixture;                -   B) an alkylamine; and                -   C) a solvent; and

    -   II) reacting the mixture.

In one aspect, provided herein is a method of preparing a compound ofFormula V, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen,halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl; andwherein at least one of R₇-R₁₀ is a halogen, the method comprising

-   -   I) forming a first mixture comprising        -   A) a compound of Formula III, wherein

-   -   -   each of R₁-R₄ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl;        -   B) a solvent; and        -   C) a halogenation reagent;

    -   II) reacting the first mixture;

    -   III) introducing a second mixture to the first mixture to form a        third mixture, the second mixture comprising        -   D) an oxidation agent; and        -   E) a catalyst; and

    -   IV) reacting the third mixture.

In one aspect, provided herein is a method of preparing a compound ofFormula VI, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen,halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl;wherein at least one of R₇-R₁₀ is a halogen; andwherein R₁₁ is selected from branched C₁-C₁₀ alkyl and unbranched C₁-C₁₀alkyl, the method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula V, wherein

-   -   -   each of R₇-R₁₀ is independently selected from hydrogen,            halogen, halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl;        -   wherein at least one of R₇-R₁₀ is a halogen; and        -   wherein the compound of Formula V is prepared according to a            method comprising            -   i) forming a mixture comprising                -   a) a compound of Formula IV, wherein

-   -   -   -   -   each of R₇-R₁₀ is independently selected from                    hydrogen, halogen, halogenated C₁-C₅ alkyl, and                    C₁-C₅ alkyl; and                -   wherein at least one of R₇-R₁₀ is a halogen;                -   b) an oxidation agent;                -   c) a solvent; and                -   d) a catalyst; and

            -   ii) reacting the mixture;

        -   B) an alkylamine; and

        -   C) a solvent; and

    -   II) reacting the mixture.

In one aspect, provided herein is a method of preparing a compound ofFormula V, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen,halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl; andwherein at least one of R₇-R₁₀ is a halogen, the method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula IV, wherein

-   -   -   each of R₇-R₁₀ is independently selected from hydrogen,            halogen, halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl; and        -   wherein at least one of R₇-R₁₀ is a halogen;        -   B) an oxidation agent;        -   C) a solvent; and        -   D) a catalyst; and

    -   II) reacting the mixture.

In one aspect, provided herein is a method of preparing a compound ofFormula IV, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen,halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl;wherein at least one of R₇-R₁₀ is a halogen, the method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula III, wherein

-   -   -   each of R₁-R₄ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl;        -   B) a solvent;        -   C) a halogenation reagent; and

    -   II) reacting the mixture.

In one aspect, provided herein is a method of preparing a compound ofFormula III, wherein

-   -   each of R₁-R₄ is independently selected from hydrogen, halogen,        and C₁-C₅ alkyl, the method comprising        -   I) forming a mixture comprising            -   A) a compound of Formula II, wherein

-   -   -   -   each of R₁-R₅ is independently selected from hydrogen,                halogen, and C₁-C₅ alkyl; and            -   wherein the compound of Formula II is prepared according                to a method comprising                -   i) forming a mixture comprising                -    a) a compound of Formula I, wherein

-   -   -   -   -    each of R₁-R₅ is independently selected from                    hydrogen, halogen, and C₁-C₅ alkyl;                -    b) chloral hydrate;                -    c) a hydroxylamine derivative;                -    d) a solvent;                -    e) an inorganic salt; and                -    f) an acid; and                -   ii) reacting the mixture; and

            -   B) an acid; and

        -   II) reacting the mixture.

In one aspect, provided herein is a method of preparing a compound ofFormula II, wherein

-   -   each of R₁-R₅ is independently selected from hydrogen, halogen,        and C₁-C₅ alkyl, the method comprising        -   I) forming a mixture comprising            -   A) a compound of Formula I, wherein

-   -   -   -   each of R₁-R₅ is independently selected from hydrogen,                halogen, and C₁-C₅ alkyl;            -   B) chloral hydrate;            -   C) a hydroxylamine derivative;            -   D) a solvent;            -   E) an inorganic salt; and            -   F) an acid; and

        -   II) reacting the mixture.

In one aspect, provided herein is a method of preparing a compound ofFormula IV, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen,halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl;wherein at least one of R₇-R₁₀ is a halogen, the method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula II, wherein

-   -   -   each of R₁-R₅ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl; and        -   B) an acid;

    -   II) reacting the first mixture;

    -   III) introducing a halogenation reagent to the first mixture to        form a second mixture; and

    -   IV) reacting the second mixture.

DETAILED DESCRIPTION OF THE DISCLOSURE

As used herein, the terms “comprises,” “comprising,” “includes,”“including,” “has,” “having,” “contains”, “containing,” “characterizedby” or any other variation thereof, are intended to cover anon-exclusive inclusion, subject to any limitation explicitly indicated.For example, a composition, mixture, process or method that comprises alist of elements is not necessarily limited to only those elements butmay include other elements not expressly listed or inherent to suchcomposition, mixture, process or method.

The transitional phrase “consisting of” excludes any element, step, oringredient not specified. If in the claim, such would close the claim tothe inclusion of materials other than those recited except forimpurities ordinarily associated therewith. When the phrase “consistingof” appears in a clause of the body of a claim, rather than immediatelyfollowing the preamble, it limits only the element set forth in thatclause; other elements are not excluded from the claim as a whole.

The transitional phrase “consisting essentially of” is used to define acomposition or method that includes materials, steps, features,components, or elements, in addition to those literally disclosed,provided that these additional materials, steps, features, components,or elements do not materially affect the basic and novelcharacteristic(s) of the claimed invention. The term “consistingessentially of” occupies a middle ground between “comprising” and“consisting of”.

Where an invention or a portion thereof is defined with an open-endedterm such as “comprising,” it should be readily understood that (unlessotherwise stated) the description should be interpreted to also describesuch an invention using the terms “consisting essentially of” or“consisting of.”

Further, unless expressly stated to the contrary, “or” refers to aninclusive or and not to an exclusive or. For example, a condition A or Bis satisfied by any one of the following: A is true (or present) and Bis false (or not present), A is false (or not present) and B is true (orpresent), and both A and B are true (or present).

Also, the indefinite articles “a” and “an” preceding an element orcomponent of the invention are intended to be nonrestrictive regardingthe number of instances (i.e. occurrences) of the element or component.Therefore “a” or “an” should be read to include one or at least one, andthe singular word form of the element or component also includes theplural unless the number is obviously meant to be singular.

As used herein, the term “about” means plus or minus 10% of the value.

The term “halogen”, either alone or in compound words such as“haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further,when used in compound words such as “haloalkyl”, said alkyl may bepartially or fully substituted with halogen atoms which may be the sameor different.

When a group contains a substituent which can be hydrogen, for exampleR⁴, then, when this substituent is taken as hydrogen, it is recognizedthat this is equivalent to said group being unsubstituted.

The term “alkyl” includes, without limitation, a functional groupcomprising straight-chain or branched alkyl. In some aspects, the alkylmay be methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentylor hexyl isomers.

Certain compounds of this invention can exist as one or morestereoisomers. The various stereoisomers include enantiomers,diastereomers, atropisomers and geometric isomers. One skilled in theart will appreciate that one stereoisomer may be more active and/or mayexhibit beneficial effects when enriched relative to the otherstereoisomer(s) or when separated from the other stereoisomer(s).Additionally, the skilled artisan knows how to separate, enrich, and/orto selectively prepare said stereoisomers.

The embodiments of this disclosure include:

Embodiment 1. A method of preparing a compound of Formula VI, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen,halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl;wherein at least one of R₇-R₁₀ is a halogen; andwherein R₁₁ is selected from branched C₁-C₁₀ alkyl and unbranched C₁-C₁₀alkyl, the method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula V, wherein

-   -   -   each of R₇-R₁₀ is independently selected from hydrogen,            halogen, halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl;        -   wherein at least one of R₇-R₁₀ is a halogen; and        -   wherein the compound of Formula V is prepared according to a            method comprising            -   i) forming a first mixture comprising                -   a) a compound of Formula III, wherein

-   -   -   -   -   each of R₁-R₄ is independently selected from                    hydrogen, halogen, and C₁-C₅ alkyl;                -   b) a solvent; and                -   c) a halogenation reagent;

            -   ii) reacting the first mixture;

            -   iii) introducing a second mixture to the first mixture                to form a third mixture, the second mixture comprising                -   d) an oxidation agent; and                -   e) a catalyst; and

            -   iv) reacting the third mixture;

        -   B) an alkylamine; and

        -   C) a solvent; and

    -   II) reacting the mixture.

Embodiment 2. The method of embodiment 1, wherein the alkylaminecomprises a functional group selected from branched C₁-C₁₀ alkyl andunbranched C₁-C₁₀ alkyl.

Embodiment 3. The method of embodiment 2, wherein the alkylamine isselected from methylamine, ethylamine, propylamine, isopropylamine,butylamine, t-butylamine, and combinations thereof.

Embodiment 4. The method of embodiment 3, wherein the alkylamine ismethylamine.

Embodiment 5. The method of embodiment 1, wherein the solvent C) isselected from acetonitrile, dichloroethane, toluene, chlorobenzene,xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropylacetate, and combinations thereof.

Embodiment 6. The method of embodiment 5, wherein the solvent C) isethyl acetate.

Embodiment 7. The method of embodiment 1, wherein the method step II) ofreacting the mixture occurs at a reaction temperature in the range ofabout 0° C. to about 100° C.

Embodiment 8. The method of embodiment 7, wherein the method step II) ofreacting the mixture occurs at a reaction temperature in the range ofabout 20° C. to about 30° C.

Embodiment 9. The method of embodiment 1, wherein the solvent b) isselected from acetonitrile, dichloroethane, toluene, chlorobenzene,xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, andcombinations thereof.

Embodiment 10. The method of embodiment 9, wherein the solvent b) isacetic acid.

Embodiment 11. The method of embodiment 1, wherein the halogenationreagent is selected from a chlorination reagent, a bromination reagent,an iodination reagent, and combinations thereof.

Embodiment 12. The method of embodiment 11, wherein the chlorinationreagent is selected from chlorine, thionyl chloride, phosgene,diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorustrichloride, phosphorus oxychloride, trichloroisocyanuric acid, andcombinations thereof.

Embodiment 13. The method of embodiment 12, wherein the chlorinationreagent is sulfuryl chloride.

Embodiment 14. The method of embodiment 1, wherein the method step ii)of reacting the first mixture occurs at a reaction temperature in therange of about 20° C. to about 140° C.

Embodiment 15. The method of embodiment 14, wherein the method step ii)of reacting the first mixture occurs at a reaction temperature in therange of about 120° C. to about 130° C.

Embodiment 16. The method of embodiment 1, wherein the oxidation agentis selected from oxygen, chlorine, sodium hypochlorite, chromiumtrioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, peroxyaceticacid, potassium peroxymonosulfate, potassium permanganate, andcombinations thereof.

Embodiment 17. The method of embodiment 16, wherein the oxidation agentis hydrogen peroxide.

Embodiment 18. The method of embodiment 1, wherein the catalyst isselected from sulfuric acid, hydrogen chloride, nitric acid, andcombinations thereof.

Embodiment 19. The method of embodiment 18, wherein the catalyst issulfuric acid.

Embodiment 20. The method of embodiment 1, wherein the method step iv)of reacting the third mixture occurs at a reaction temperature in therange of about 20° C. to about 100° C.

Embodiment 21. The method of embodiment 20, wherein the method step iv)of reacting the third mixture occurs at a reaction temperature in therange of about 60° C. to about 65° C.

Embodiment 22. The method of embodiment 1, wherein the compound ofFormula III is prepared according to a method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula II, wherein

-   -   -   each of R₁-R₅ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl; and        -   wherein the compound of Formula II is prepared according to            a method comprising            -   i) forming a mixture comprising                -   a) a compound of Formula I, wherein

-   -   -   -   -   each of R₁-R₅ is independently selected from                    hydrogen, halogen, and C₁-C₅ alkyl;                -   b) chloral hydrate;                -   c) a hydroxylamine derivative;                -   d) a solvent;                -   e) an inorganic salt; and                -   f) an acid; and

            -   ii) reacting the mixture; and

        -   B) an acid; and

    -   II) reacting the mixture.

Embodiment 23. The method of embodiment 22, wherein the acid B) isselected from hydrochloric acid, sulfuric acid, nitric acid, aceticacid, and combinations thereof.

Embodiment 24. The method of embodiment 23, wherein the acid B) ishydrochloric acid.

Embodiment 25. The method of embodiment 22, wherein the method step II)of reacting the mixture occurs at a reaction temperature in the range ofabout 10° C. to about 90° C.

Embodiment 26. The method of embodiment 25, wherein the method step II)of reacting the mixture occurs at a reaction temperature in the range ofabout 60° C. to about 65° C.

Embodiment 27. The method of embodiment 22, wherein the hydroxylaminederivative is selected from hydroxylamine sulfate, hydroxylaminehydrochloride, and combinations thereof.

Embodiment 28. The method of embodiment 27, wherein the hydroxylaminederivative is hydroxylamine sulfate.

Embodiment 29. The method of embodiment 22, wherein the solvent isselected from methanol, ethanol, toluene, water, and combinationsthereof.

Embodiment 30. The method of embodiment 29, wherein the solvent iswater.

Embodiment 31. The method of embodiment 22, wherein the inorganic saltis selected from sodium sulfate, sodium hydrogen sulfate, sodiumchloride, sodium disulfite, potassium sulfate, potassium chloride, andcombinations thereof.

Embodiment 32. The method of embodiment 31, wherein the inorganic saltis sodium sulfate.

Embodiment 33. The method of embodiment 22, wherein the acid f) isselected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromicacid, formic acid, acetic acid, and combinations thereof.

Embodiment 34. The method of embodiment 33, wherein the acid f) ishydrochloric acid.

Embodiment 35. The method of embodiment 22, wherein the concentration ofthe compound of Formula I in the mixture ranges from about 1% to about30%.

Embodiment 36. The method of embodiment 35, wherein the concentration ofthe compound of Formula I in the mixture is in the range of about 3% toabout 10%.

Embodiment 37. The method of embodiment 22, wherein the method step ii)of reacting the mixture occurs at a reaction temperature in the range ofabout 10° C. to about 100° C.

Embodiment 38. The method of embodiment 37, wherein the method step ii)of reacting the mixture occurs at a reaction temperature in the range ofabout 50° C. to about 55° C.

Embodiment 39. A method of preparing a compound of Formula V, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen,halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl; andwherein at least one of R₇-R₁₀ is a halogen, the method comprising

-   -   I) forming a first mixture comprising        -   A) a compound of Formula III, wherein

-   -   -   each of R₁-R₄ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl;        -   B) a solvent; and        -   C) a halogenation reagent;

    -   II) reacting the first mixture;

    -   III) introducing a second mixture to the first mixture to form a        third mixture, the second mixture comprising        -   D) an oxidation agent; and        -   E) a catalyst; and

    -   IV) reacting the third mixture.

Embodiment 40. The method of embodiment 39, wherein the solvent isselected from acetonitrile, dichloroethane, toluene, chlorobenzene,xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, andcombinations thereof.

Embodiment 41. The method of embodiment 40, wherein the solvent isacetic acid.

Embodiment 42. The method of embodiment 39, wherein the halogenationreagent is selected from a chlorination reagent, a bromination reagent,an iodination reagent, and combinations thereof.

Embodiment 43. The method of embodiment 42, wherein the chlorinationreagent is selected from chlorine, thionyl chloride, phosgene,diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorustrichloride, phosphorus oxychloride, trichloroisocyanuric acid, andcombinations thereof.

Embodiment 44. The method of embodiment 43, wherein the chlorinationreagent is sulfuryl chloride.

Embodiment 45. The method of embodiment 39, wherein the method step II)of reacting the first mixture occurs at a reaction temperature in therange of about 20° C. to about 140° C.

Embodiment 46. The method of embodiment 45, wherein the method step II)of reacting the first mixture occurs at a reaction temperature in therange of about 120° C. to about 130° C.

Embodiment 47. The method of embodiment 39, wherein the oxidation agentis selected from oxygen, chlorine, sodium hypochlorite, chromiumtrioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, peroxyaceticacid, potassium peroxymonosulfate, potassium permanganate, andcombinations thereof.

Embodiment 48. The method of embodiment 47, wherein the oxidation agentis hydrogen peroxide.

Embodiment 49. The method of embodiment 39, wherein the catalyst isselected from sulfuric acid, hydrogen chloride, nitric acid, andcombinations thereof.

Embodiment 50. The method of embodiment 49, wherein the catalyst issulfuric acid.

Embodiment 51. The method of embodiment 39, wherein the method step IV)of reacting the third mixture occurs at a reaction temperature in therange of about 20° C. to about 100° C.

Embodiment 52. The method of embodiment 51, wherein the method step IV)of reacting the third mixture occurs at a reaction temperature in therange of about 60° C. to about 65° C.

Embodiment 53. The method of embodiment 39, wherein the compound ofFormula III is prepared according to a method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula II, wherein

-   -   -   each of R₁-R₅ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl; and        -   wherein the compound of Formula II is prepared according to            a method comprising            -   i) forming a mixture comprising                -   a) a compound of Formula I, wherein

-   -   -   -   -   each of R₁-R₅ is independently selected from                    hydrogen, halogen, and C₁-C₅ alkyl;                -   b) chloral hydrate;                -   c) a hydroxylamine derivative;                -   d) a solvent;                -   e) an inorganic salt; and                -   f) an acid; and

            -   ii) reacting the mixture; and

        -   B) an acid; and

    -   II) reacting the mixture.

Embodiment 54. The method of embodiment 53, wherein the acid B) isselected from hydrochloric acid, sulfuric acid, nitric acid, aceticacid, and combinations thereof.

Embodiment 55. The method of embodiment 54, wherein the acid B) ishydrochloric acid.

Embodiment 56. The method of embodiment 53, wherein the method step II)of reacting the mixture occurs at a reaction temperature in the range ofabout 10° C. to about 90° C.

Embodiment 57. The method of embodiment 56, wherein the method step II)of reacting the mixture occurs at a reaction temperature in the range ofabout 60° C. to about 65° C.

Embodiment 58. The method of embodiment 53, wherein the hydroxylaminederivative is selected from hydroxylamine sulfate, hydroxylaminehydrochloride, and combinations thereof.

Embodiment 59. The method of embodiment 58, wherein the hydroxylaminederivative is hydroxylamine sulfate.

Embodiment 60. The method of embodiment 53, wherein the solvent isselected from methanol, ethanol, toluene, water, and combinationsthereof.

Embodiment 61. The method of embodiment 60, wherein the solvent iswater.

Embodiment 62. The method of embodiment 53, wherein the inorganic saltis selected from sodium sulfate, sodium hydrogen sulfate, sodiumchloride, sodium disulfite, potassium sulfate, potassium chloride, andcombinations thereof.

Embodiment 63. The method of embodiment 62, wherein the inorganic saltis sodium sulfate.

Embodiment 64. The method of embodiment 53, wherein the acid f) isselected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromicacid, formic acid, acetic acid, and combinations thereof.

Embodiment 65. The method of embodiment 64, wherein the acid f) ishydrochloric acid.

Embodiment 66. The method of embodiment 53, wherein the concentration ofthe compound of Formula I in the mixture ranges from about 1% to about30%.

Embodiment 67. The method of embodiment 66, wherein the concentration ofthe compound of Formula I in the mixture is in the range of about 3% toabout 10%.

Embodiment 68. The method of embodiment 53, wherein the method step ii)of reacting the mixture occurs at a reaction temperature in the range ofabout 10° C. to about 100° C.

Embodiment 69. The method of embodiment 68, wherein the method step ii)of reacting the mixture occurs at a reaction temperature in the range ofabout 50° C. to about 55° C.

Embodiment 70. A method of preparing a compound of Formula VI, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen,halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl;wherein at least one of R₇-R₁₀ is a halogen; andwherein R₁₁ is selected from branched C₁-C₁₀ alkyl and unbranched C₁-C₁₀alkyl, the method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula V, wherein

-   -   -   each of R₇-R₁₀ is independently selected from hydrogen,            halogen, halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl;        -   wherein at least one of R₇-R₁₀ is a halogen; and        -   wherein the compound of Formula V is prepared according to a            method comprising            -   i) forming a mixture comprising                -   a) a compound of Formula IV, wherein

-   -   -   -   -   each of R₇-R₁₀ is independently selected from                    hydrogen, halogen, halogenated C₁-C₅ alkyl, and                    C₁-C₅ alkyl; and                -   wherein at least one of R₇-R₁₀ is a halogen;                -   b) an oxidation agent;                -   c) a solvent; and                -   d) a catalyst; and

            -   ii) reacting the mixture;

        -   B) an alkylamine; and

        -   C) a solvent; and

    -   II) reacting the mixture.

Embodiment 71. The method of embodiment 70, wherein the alkylaminecomprises a functional group selected from branched C₁-C₁₀ alkyl andunbranched C₁-C₁₀ alkyl.

Embodiment 72. The method of embodiment 71, wherein the alkylamine isselected from methylamine, ethylamine, propylamine, isopropylamine,butylamine, t-butylamine, and combinations thereof.

Embodiment 73. The method of embodiment 72, wherein the alkylamine ismethylamine.

Embodiment 74. The method of embodiment 70, wherein the solvent C) isselected from acetonitrile, dichloroethane, toluene, chlorobenzene,xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropylacetate, and combinations thereof.

Embodiment 75. The method of embodiment 74, wherein the solvent C) isethyl acetate.

Embodiment 76. The method of embodiment 70, wherein the method step II)of reacting the mixture occurs at a reaction temperature in the range ofabout 0° C. to about 100° C.

Embodiment 77. The method of embodiment 76, wherein the method step II)of reacting the mixture occurs at a reaction temperature in the range ofabout 20° C. to about 30° C.

Embodiment 78. The method of embodiment 70, wherein the oxidation agentis selected from oxygen, chlorine, sodium hypochlorite, chromiumtrioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, peroxyaceticacid, potassium peroxymonosulfate, potassium permanganate, andcombinations thereof.

Embodiment 79. The method of embodiment 78, wherein the oxidation agentis hydrogen peroxide.

Embodiment 80. The method of embodiment 70, wherein the solvent c) isselected from acetonitrile, methanol, ethanol, isopropanol, water,dimethylformamide, dimethyl sulfoxide, N-Methylpyrrolidone,tetrahydrofuran, acetic acid, acetic anhydride, propionic acid, butyricacid, and combinations thereof.

Embodiment 81. The method of embodiment 80, wherein the solvent c) isacetic acid.

Embodiment 82. The method of embodiment 70, wherein the catalyst isselected from sulfuric acid, hydrogen chloride, nitric acid, andcombinations thereof.

Embodiment 83. The method of embodiment 82, wherein the catalyst issulfuric acid.

Embodiment 84. The method of embodiment 70, wherein the method step ii)of reacting the mixture occurs at a reaction temperature in the range ofabout 20° C. to about 100° C.

Embodiment 85. The method of embodiment 84, wherein the method step ii)of reacting the mixture occurs at a reaction temperature in the range ofabout 60° C. to about 65° C.

Embodiment 86. The method of embodiment 70, wherein the compound ofFormula IV is prepared according to a method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula III, wherein

-   -   -   each of R₁-R₄ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl;        -   B) a solvent;        -   C) a halogenation reagent; and

    -   II) reacting the mixture.

Embodiment 87. The method of embodiment 86, wherein the solvent isselected from acetonitrile, dichloroethane, toluene, chlorobenzene,xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, andcombinations thereof.

Embodiment 88. The method of embodiment 87, wherein the solvent isacetic acid.

Embodiment 89. The method of embodiment 86, wherein the halogenationreagent is selected from a chlorination reagent, a bromination reagent,an iodination reagent, and combinations thereof.

Embodiment 90. The method of embodiment 89, wherein the chlorinationreagent is selected from chlorine, thionyl chloride, phosgene,diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorustrichloride, phosphorus oxychloride, trichloroisocyanuric acid, andcombinations thereof.

Embodiment 91. The method of embodiment 90, wherein the chlorinationreagent is sulfuryl chloride.

Embodiment 92. The method of embodiment 86, wherein the method step II)of reacting the mixture occurs at a reaction temperature in the range ofabout 20° C. to about 140° C.

Embodiment 93. The method of embodiment 92, wherein the method step II)of reacting the mixture occurs at a reaction temperature in the range ofabout 120° C. to about 130° C.

Embodiment 94. The method of embodiment 86, wherein the compound ofFormula III is prepared according to a method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula II, wherein

-   -   -   each of R₁-R₅ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl; and        -   wherein the compound of Formula II is prepared according to            a method comprising            -   i) forming a mixture comprising                -   a) a compound of Formula I, wherein

-   -   -   -   -   each of R₁-R₅ is independently selected from                    hydrogen, halogen, and C₁-C₅ alkyl;                -   b) chloral hydrate;                -   c) a hydroxylamine derivative;                -   d) a solvent;                -   e) an inorganic salt; and                -   f) an acid; and

            -   ii) reacting the mixture; and

        -   B) an acid; and

    -   II) reacting the mixture.

Embodiment 95. The method of embodiment 94, wherein the acid B) isselected from hydrochloric acid, sulfuric acid, nitric acid, aceticacid, and combinations thereof.

Embodiment 96. The method of embodiment 95, wherein the acid B) ishydrochloric acid.

Embodiment 97. The method of embodiment 94, wherein the method step II)of reacting the mixture occurs at a reaction temperature in the range ofabout 10° C. to about 90° C.

Embodiment 98. The method of embodiment 97, wherein the method step II)of reacting the mixture occurs at a reaction temperature in the range ofabout 60° C. to about 65° C.

Embodiment 99. The method of embodiment 94, wherein the hydroxylaminederivative is selected from hydroxylamine sulfate, hydroxylaminehydrochloride, and combinations thereof.

Embodiment 100. The method of embodiment 99, wherein the hydroxylaminederivative is hydroxylamine sulfate.

Embodiment 101. The method of embodiment 94, wherein the solvent isselected from methanol, ethanol, toluene, water, and combinationsthereof.

Embodiment 102. The method of embodiment 101, wherein the solvent iswater.

Embodiment 103. The method of embodiment 94, wherein the inorganic saltis selected from sodium sulfate, sodium hydrogen sulfate, sodiumchloride, sodium disulfite, potassium sulfate, potassium chloride, andcombinations thereof.

Embodiment 104. The method of embodiment 103, wherein the inorganic saltis sodium sulfate.

Embodiment 105. The method of embodiment 94, wherein the acid f) isselected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromicacid, formic acid, acetic acid, and combinations thereof.

Embodiment 106. The method of embodiment 105, wherein the acid f) ishydrochloric acid.

Embodiment 107. The method of embodiment 94, wherein the concentrationof the compound of Formula I in the mixture ranges from about 1% toabout 30%.

Embodiment 108. The method of embodiment 107, wherein the concentrationof the compound of Formula I in the mixture is in the range of about 3%to about 10%.

Embodiment 109. The method of embodiment 94, wherein the method step ii)of reacting the mixture occurs at a reaction temperature in the range ofabout 10° C. to about 100° C.

Embodiment 110. The method of embodiment 109, wherein the method stepii) of reacting the mixture occurs at a reaction temperature in therange of about 50° C. to about 55° C.

Embodiment 111. The method of embodiment 70, wherein the compound ofFormula IV is prepared according to a method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula II, wherein

-   -   -   each of R₁-R₅ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl; and        -   B) an acid;

    -   II) reacting the first mixture;

    -   III) introducing a halogenation reagent to the first mixture to        form a second mixture; and

    -   IV) reacting the second mixture.

Embodiment 112. The method of embodiment 111, wherein the acid isselected from sulfuric acid, acetic acid, and combinations thereof.

Embodiment 113. The method of embodiment 112, wherein the acid issulfuric acid.

Embodiment 114. The method of embodiment 111, wherein the halogenationreagent is selected from a chlorination reagent, a bromination reagent,an iodination reagent, and combinations thereof.

Embodiment 115. The method of embodiment 114, wherein the chlorinationreagent is selected from chlorine, thionyl chloride, phosgene,diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorustrichloride, phosphorus oxychloride, trichloroisocyanuric acid, andcombinations thereof.

Embodiment 116. The method of embodiment 115, wherein the chlorinationreagent is trichloroisocyanuric acid.

Embodiment 117. The method of embodiment 111, wherein the method stepIV) of reacting the second mixture occurs at a reaction temperature inthe range of about 10° C. to about 100° C.

Embodiment 118. The method of embodiment 117, wherein the method stepIV) of reacting the second mixture occurs at a reaction temperature inthe range of about 10° C. to about 65° C.

Embodiment 119. The method of embodiment 111, wherein the compound ofFormula II is prepared according to a method comprising

-   -   i) forming a mixture comprising        -   a) a compound of Formula I, wherein

-   -   -   each of R₁-R₅ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl;        -   b) chloral hydrate;        -   c) a hydroxylamine derivative;        -   d) a solvent;        -   e) an inorganic salt; and        -   f) an acid; and

    -   ii) reacting the mixture.

Embodiment 120. The method of embodiment 119, wherein the hydroxylaminederivative is selected from hydroxylamine sulfate, hydroxylaminehydrochloride, and combinations thereof.

Embodiment 121. The method of embodiment 120, wherein the hydroxylaminederivative is hydroxylamine sulfate.

Embodiment 122. The method of embodiment 119, wherein the solvent isselected from methanol, ethanol, toluene, water, and combinationsthereof.

Embodiment 123. The method of embodiment 122, wherein the solvent iswater.

Embodiment 124. The method of embodiment 119, wherein the inorganic saltis selected from sodium sulfate, sodium hydrogen sulfate, sodiumchloride, sodium disulfite, potassium sulfate, potassium chloride, andcombinations thereof.

Embodiment 125. The method of embodiment 124, wherein the inorganic saltis sodium sulfate.

Embodiment 126. The method of embodiment 119, wherein the acid isselected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromicacid, formic acid, acetic acid, and combinations thereof.

Embodiment 127. The method of embodiment 126, wherein the acid ishydrochloric acid.

Embodiment 128. The method of embodiment 119, wherein the concentrationof the compound of Formula I in the mixture ranges from about 1% toabout 30%.

Embodiment 129. The method of embodiment 128, wherein the concentrationof the compound of Formula I in the mixture is in the range of about 3%to about 10%.

Embodiment 130. The method of embodiment 119, wherein the method step ofreacting the mixture occurs at a reaction temperature in the range ofabout 10° C. to about 100° C.

Embodiment 131. The method of embodiment 130, wherein the method step ofreacting the mixture occurs at a reaction temperature in the range ofabout 50° C. to about 55° C.

Embodiment 132. A method of preparing a compound of Formula V, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen,halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl; andwherein at least one of R₇-R₁₀ is a halogen, the method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula IV, wherein

-   -   -   each of R₇-R₁₀ is independently selected from hydrogen,            halogen, halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl; and        -   wherein at least one of R₇-R₁₀ is a halogen;        -   B) an oxidation agent;        -   C) a solvent; and        -   D) a catalyst; and

    -   II) reacting the mixture.

Embodiment 133. The method of embodiment 132, wherein the oxidationagent is selected from oxygen, chlorine, sodium hypochlorite, chromiumtrioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, peroxyaceticacid, potassium peroxymonosulfate, potassium permanganate, andcombinations thereof.

Embodiment 134. The method of embodiment 133, wherein the oxidationagent is hydrogen peroxide.

Embodiment 135. The method of embodiment 132, wherein the solvent isselected from acetonitrile, methanol, ethanol, isopropanol, water,dimethylformamide, dimethyl sulfoxide, N-Methylpyrrolidone,tetrahydrofuran, acetic acid, acetic anhydride, propionic acid, butyricacid, and combinations thereof.

Embodiment 136. The method of embodiment 135, wherein the solvent isacetic acid.

Embodiment 137. The method of embodiment 132, wherein the catalyst isselected from sulfuric acid, hydrogen chloride, nitric acid, andcombinations thereof.

Embodiment 138. The method of embodiment 137, wherein the catalyst issulfuric acid.

Embodiment 139. The method of embodiment 132, wherein the method stepII) of reacting the mixture occurs at a reaction temperature in therange of about 20° C. to about 100° C.

Embodiment 140. The method of embodiment 139, wherein the method stepII) of reacting the mixture occurs at a reaction temperature in therange of about 60° C. to about 65° C.

Embodiment 141. The method of embodiment 132, wherein the compound ofFormula IV is prepared according to a method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula III, wherein

-   -   -   each of R₁-R₄ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl;

    -   B) a solvent;

    -   C) a halogenation reagent; and

    -   II) reacting the mixture.

Embodiment 142. The method of embodiment 141, wherein the solvent isselected from acetonitrile, dichloroethane, toluene, chlorobenzene,xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, andcombinations thereof.

Embodiment 143. The method of embodiment 142, wherein the solvent isacetic acid.

Embodiment 144. The method of embodiment 141, wherein the halogenationreagent is selected from a chlorination reagent, a bromination reagent,an iodination reagent, and combinations thereof.

Embodiment 145. The method of embodiment 144, wherein the chlorinationreagent is selected from chlorine, thionyl chloride, phosgene,diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorustrichloride, phosphorus oxychloride, trichloroisocyanuric acid, andcombinations thereof.

Embodiment 146. The method of embodiment 145, wherein the chlorinationreagent is sulfuryl chloride.

Embodiment 147. The method of embodiment 141, wherein the method stepII) of reacting the mixture occurs at a reaction temperature in therange of about 20° C. to about 140° C.

Embodiment 148. The method of embodiment 147, wherein the method stepII) of reacting the mixture occurs at a reaction temperature in therange of about 120° C. to about 130° C.

Embodiment 149. The method of embodiment 141, wherein the compound ofFormula III is prepared according to a method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula II, wherein

-   -   -   each of R₁-R₅ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl; and        -   wherein the compound of Formula II is prepared according to            a method comprising            -   i) forming a mixture comprising                -   a) a compound of Formula I, wherein

-   -   -   -   -   each of R₁-R₅ is independently selected from                    hydrogen, halogen, and C₁-C₅ alkyl;                -   b) chloral hydrate;                -   c) a hydroxylamine derivative;                -   d) a solvent;                -   e) an inorganic salt; and                -   f) an acid; and

            -   ii) reacting the mixture; and

        -   B) an acid; and

    -   II) reacting the mixture.

Embodiment 150. The method of embodiment 149, wherein the acid B) isselected from hydrochloric acid, sulfuric acid, nitric acid, aceticacid, and combinations thereof.

Embodiment 151. The method of embodiment 150, wherein the acid B) ishydrochloric acid.

Embodiment 152. The method of embodiment 149, wherein the method stepII) of reacting the mixture occurs at a reaction temperature in therange of about 10° C. to about 90° C.

Embodiment 153. The method of embodiment 152, wherein the method stepII) of reacting the mixture occurs at a reaction temperature in therange of about 60° C. to about 65° C.

Embodiment 154. The method of embodiment 149, wherein the hydroxylaminederivative is selected from hydroxylamine sulfate, hydroxylaminehydrochloride, and combinations thereof.

Embodiment 155. The method of embodiment 154, wherein the hydroxylaminederivative is hydroxylamine sulfate.

Embodiment 156. The method of embodiment 149, wherein the solvent isselected from methanol, ethanol, toluene, water, and combinationsthereof.

Embodiment 157. The method of embodiment 156, wherein the solvent iswater.

Embodiment 158. The method of embodiment 149, wherein the inorganic saltis selected from sodium sulfate, sodium hydrogen sulfate, sodiumchloride, sodium disulfite, potassium sulfate, potassium chloride, andcombinations thereof.

Embodiment 159. The method of embodiment 158, wherein the inorganic saltis sodium sulfate.

Embodiment 160. The method of embodiment 149, wherein the acid f) isselected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromicacid, formic acid, acetic acid, and combinations thereof.

Embodiment 161. The method of embodiment 160, wherein the acid f) ishydrochloric acid.

Embodiment 162. The method of embodiment 149, wherein the concentrationof the compound of Formula I in the mixture ranges from about 1% toabout 30%.

Embodiment 163. The method of embodiment 162, wherein the concentrationof the compound of Formula I in the mixture is in the range of about 3%to about 10%.

Embodiment 164. The method of embodiment 149, wherein the method stepii) of reacting the mixture occurs at a reaction temperature in therange of about 10° C. to about 100° C.

Embodiment 165. The method of embodiment 164, wherein the method stepii) of reacting the mixture occurs at a reaction temperature in therange of about 50° C. to about 55° C.

Embodiment 166. The method of embodiment 132, wherein the compound ofFormula IV is prepared according to a method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula II, wherein

-   -   -   each of R₁-R₅ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl; and        -   B) an acid;

    -   II) reacting the first mixture;

    -   III) introducing a halogenation reagent to the first mixture to        form a second mixture; and

    -   IV) reacting the second mixture.

Embodiment 167. The method of embodiment 166, wherein the acid isselected from sulfuric acid, acetic acid, and combinations thereof.

Embodiment 168. The method of embodiment 167, wherein the acid issulfuric acid.

Embodiment 169. The method of embodiment 166, wherein the halogenationreagent is selected from a chlorination reagent, a bromination reagent,an iodination reagent, and combinations thereof.

Embodiment 170. The method of embodiment 169, wherein the chlorinationreagent is selected from chlorine, thionyl chloride, phosgene,diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorustrichloride, phosphorus oxychloride, trichloroisocyanuric acid, andcombinations thereof.

Embodiment 171. The method of embodiment 170, wherein the chlorinationreagent is trichloroisocyanuric acid.

Embodiment 172. The method of embodiment 166, wherein the method stepIV) of reacting the second mixture occurs at a reaction temperature inthe range of about 10° C. to about 100° C.

Embodiment 173. The method of embodiment 172, wherein the method stepIV) of reacting the second mixture occurs at a reaction temperature inthe range of about 10° C. to about 65° C.

Embodiment 174. The method of embodiment 166, wherein the compound ofFormula II is prepared according to a method comprising

-   -   i) forming a mixture comprising        -   a) a compound of Formula I, wherein

-   -   -   each of R₁-R₅ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl;        -   b) chloral hydrate;        -   c) a hydroxylamine derivative;        -   d) a solvent;        -   e) an inorganic salt; and        -   f) an acid; and

    -   ii) reacting the mixture.

Embodiment 175. The method of embodiment 174, wherein the hydroxylaminederivative is selected from hydroxylamine sulfate, hydroxylaminehydrochloride, and combinations thereof.

Embodiment 176. The method of embodiment 175, wherein the hydroxylaminederivative is hydroxylamine sulfate.

Embodiment 177. The method of embodiment 174, wherein the solvent isselected from methanol, ethanol, toluene, water, and combinationsthereof.

Embodiment 178. The method of embodiment 177, wherein the solvent iswater.

Embodiment 179. The method of embodiment 174, wherein the inorganic saltis selected from sodium sulfate, sodium hydrogen sulfate, sodiumchloride, sodium disulfite, potassium sulfate, potassium chloride, andcombinations thereof.

Embodiment 180. The method of embodiment 179, wherein the inorganic saltis sodium sulfate.

Embodiment 181. The method of embodiment 174, wherein the acid isselected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromicacid, formic acid, acetic acid, and combinations thereof.

Embodiment 182. The method of embodiment 181, wherein the acid ishydrochloric acid.

Embodiment 183. The method of embodiment 174, wherein the concentrationof the compound of Formula I in the mixture ranges from about 1% toabout 30%.

Embodiment 184. The method of embodiment 183, wherein the concentrationof the compound of Formula I in the mixture is in the range of about 3%to about 10%.

Embodiment 185. The method of embodiment 174, wherein the method step ofreacting the mixture occurs at a reaction temperature in the range ofabout 10° C. to about 100° C.

Embodiment 186. The method of embodiment 185, wherein the method step ofreacting the mixture occurs at a reaction temperature in the range ofabout 50° C. to about 55° C.

Embodiment 187. A method of preparing a compound of Formula IV, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen,halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl;wherein at least one of R₇-R₁₀ is a halogen, the method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula III, wherein

-   -   -   each of R₁-R₄ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl;        -   B) a solvent;        -   C) a halogenation reagent; and

    -   II) reacting the mixture.

Embodiment 188. The method of embodiment 187, wherein the solvent isselected from acetonitrile, dichloroethane, toluene, chlorobenzene,xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, andcombinations thereof.

Embodiment 189. The method of embodiment 188, wherein the solvent isacetic acid.

Embodiment 190. The method of embodiment 187, wherein the halogenationreagent is selected from a chlorination reagent, a bromination reagent,an iodination reagent, and combinations thereof.

Embodiment 191. The method of embodiment 190, wherein the chlorinationreagent is selected from chlorine, thionyl chloride, phosgene,diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorustrichloride, phosphorus oxychloride, trichloroisocyanuric acid, andcombinations thereof.

Embodiment 192. The method of embodiment 191, wherein the chlorinationreagent is sulfuryl chloride.

Embodiment 193. The method of embodiment 187, wherein the method stepII) of reacting the mixture occurs at a reaction temperature in therange of about 20° C. to about 140° C.

Embodiment 194. The method of embodiment 193, wherein the method stepII) of reacting the mixture occurs at a reaction temperature in therange of about 120° C. to about 130° C.

Embodiment 195. The method of embodiment 187, wherein the compound ofFormula III is prepared according to a method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula II, wherein

-   -   -   each of R₁-R₅ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl; and        -   wherein the compound of Formula II is prepared according to            a method comprising            -   i) forming a mixture comprising                -   a) a compound of Formula I, wherein

-   -   -   -   -   each of R₁-R₅ is independently selected from                    hydrogen, halogen, and C₁-C₅ alkyl;                -   b) chloral hydrate;                -   c) a hydroxylamine derivative;                -   d) a solvent;                -   e) an inorganic salt; and                -   f) an acid; and

            -   ii) reacting the mixture; and

        -   B) an acid; and

    -   II) reacting the mixture.

Embodiment 196. The method of embodiment 195, wherein the acid B) isselected from hydrochloric acid, sulfuric acid, nitric acid, aceticacid, and combinations thereof.

Embodiment 197. The method of embodiment 196, wherein the acid B) ishydrochloric acid.

Embodiment 198. The method of embodiment 195, wherein the method stepII) of reacting the mixture occurs at a reaction temperature in therange of about 10° C. to about 90° C.

Embodiment 199. The method of embodiment 198, wherein the method stepII) of reacting the mixture occurs at a reaction temperature in therange of about 60° C. to about 65° C.

Embodiment 200. The method of embodiment 195, wherein the hydroxylaminederivative is selected from hydroxylamine sulfate, hydroxylaminehydrochloride, and combinations thereof.

Embodiment 201. The method of embodiment 200, wherein the hydroxylaminederivative is hydroxylamine sulfate.

Embodiment 202. The method of embodiment 195, wherein the solvent isselected from methanol, ethanol, toluene, water, and combinationsthereof.

Embodiment 203. The method of embodiment 202, wherein the solvent iswater.

Embodiment 204. The method of embodiment 195, wherein the inorganic saltis selected from sodium sulfate, sodium hydrogen sulfate, sodiumchloride, sodium disulfite, potassium sulfate, potassium chloride, andcombinations thereof.

Embodiment 205. The method of embodiment 204, wherein the inorganic saltis sodium sulfate.

Embodiment 206. The method of embodiment 195, wherein the acid f) isselected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromicacid, formic acid, acetic acid, and combinations thereof.

Embodiment 207. The method of embodiment 206, wherein the acid f) ishydrochloric acid.

Embodiment 208. The method of embodiment 195, wherein the concentrationof the compound of Formula I in the mixture ranges from about 1% toabout 30%.

Embodiment 209. The method of embodiment 208, wherein the concentrationof the compound of Formula I in the mixture is in the range of about 3%to about 10%.

Embodiment 210. The method of embodiment 195, wherein the method stepii) of reacting the mixture occurs at a reaction temperature in therange of about 10° C. to about 100° C.

Embodiment 211. The method of embodiment 210, wherein the method stepii) of reacting the mixture occurs at a reaction temperature in therange of about 50° C. to about 55° C.

Embodiment 212. A method of preparing a compound of Formula III, wherein

each of R₁-R₄ is independently selected from hydrogen, halogen, andC₁-C₅ alkyl, the method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula II, wherein

-   -   -   each of R₁-R₅ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl; and        -   wherein the compound of Formula II is prepared according to            a method comprising            -   i) forming a mixture comprising                -   a) a compound of Formula I, wherein

-   -   -   -   -   each of R₁-R₅ is independently selected from                    hydrogen, halogen, and C₁-C₅ alkyl;                -   b) chloral hydrate;                -   c) a hydroxylamine derivative;                -   d) a solvent;                -   e) an inorganic salt; and                -   f) an acid; and

            -   ii) reacting the mixture; and

        -   B) an acid; and

    -   II) reacting the mixture.

Embodiment 213. The method of embodiment 212, wherein the acid B) isselected from hydrochloric acid, sulfuric acid, nitric acid, aceticacid, and combinations thereof.

Embodiment 214. The method of embodiment 213, wherein the acid B) ishydrochloric acid.

Embodiment 215. The method of embodiment 212, wherein the method stepII) of reacting the mixture occurs at a reaction temperature in therange of about 10° C. to about 90° C.

Embodiment 216. The method of embodiment 215, wherein the method stepII) of reacting the mixture occurs at a reaction temperature in therange of about 60° C. to about 65° C.

Embodiment 217. The method of embodiment 212, wherein the hydroxylaminederivative is selected from hydroxylamine sulfate, hydroxylaminehydrochloride, and combinations thereof.

Embodiment 218. The method of embodiment 217, wherein the hydroxylaminederivative is hydroxylamine sulfate.

Embodiment 219. The method of embodiment 212, wherein the solvent isselected from methanol, ethanol, toluene, water, and combinationsthereof.

Embodiment 220. The method of embodiment 219, wherein the solvent iswater.

Embodiment 221. The method of embodiment 212, wherein the inorganic saltis selected from sodium sulfate, sodium hydrogen sulfate, sodiumchloride, sodium disulfite, potassium sulfate, potassium chloride, andcombinations thereof.

Embodiment 222. The method of embodiment 221, wherein the inorganic saltis sodium sulfate.

Embodiment 223. The method of embodiment 212, wherein the acid f) isselected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromicacid, formic acid, acetic acid, and combinations thereof.

Embodiment 224. The method of embodiment 223, wherein the acid f) ishydrochloric acid.

Embodiment 225. The method of embodiment 212, wherein the concentrationof the compound of Formula I in the mixture ranges from about 1% toabout 30%.

Embodiment 226. The method of embodiment 225, wherein the concentrationof the compound of Formula I in the mixture is in the range of about 3%to about 10%.

Embodiment 227. The method of embodiment 212, wherein the method stepii) of reacting the mixture occurs at a reaction temperature in therange of about 10° C. to about 100° C.

Embodiment 228. The method of embodiment 227, wherein the method stepii) of reacting the mixture occurs at a reaction temperature in therange of about 50° C. to about 55° C.

Embodiment 229. A method of preparing a compound of Formula II, wherein

each of R₁-R₅ is independently selected from hydrogen, halogen, andC₁-C₅ alkyl, the method comprising

-   -   I) forming a mixture comprising        -   A) a compound of Formula I, wherein

-   -   -   each of R₁-R₅ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl;        -   B) chloral hydrate;        -   C) a hydroxylamine derivative;        -   D) a solvent;        -   E) an inorganic salt; and        -   F) an acid; and

    -   II) reacting the mixture.

Embodiment 230. The method of embodiment 229, wherein the hydroxylaminederivative is selected from hydroxylamine sulfate, hydroxylaminehydrochloride, and combinations thereof.

Embodiment 231. The method of embodiment 230, wherein the hydroxylaminederivative is hydroxylamine sulfate.

Embodiment 232. The method of embodiment 229, wherein the solvent isselected from methanol, ethanol, toluene, water, and combinationsthereof.

Embodiment 233. The method of embodiment 232, wherein the solvent iswater.

Embodiment 234. The method of embodiment 229, wherein the inorganic saltis selected from sodium sulfate, sodium hydrogen sulfate, sodiumchloride, sodium disulfite, potassium sulfate, potassium chloride, andcombinations thereof.

Embodiment 235. The method of embodiment 234, wherein the inorganic saltis sodium sulfate.

Embodiment 236. The method of embodiment 229, wherein the acid isselected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromicacid, formic acid, acetic acid, and combinations thereof.

Embodiment 237. The method of embodiment 236, wherein the acid ishydrochloric acid.

Embodiment 238. The method of embodiment 229, wherein the concentrationof the compound of Formula I in the mixture ranges from about 1% toabout 30%.

Embodiment 239. The method of embodiment 238, wherein the concentrationof the compound of Formula I in the mixture is in the range of about 3%to about 10%.

Embodiment 240. The method of embodiment 229, wherein the method step ofreacting the mixture occurs at a reaction temperature in the range ofabout 10° C. to about 100° C.

Embodiment 241. The method of embodiment 240, wherein the method step ofreacting the mixture occurs at a reaction temperature in the range ofabout 50° C. to about 55° C.

Embodiment 242. A method of preparing a compound of Formula IV, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen,halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl;wherein at least one of R₇-R₁₀ is a halogen, the method comprising

-   -   I) forming a first mixture comprising        -   A) a compound of Formula II, wherein

-   -   -   each of R₁-R₅ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl; and        -   B) an acid;

    -   II) reacting the first mixture;

    -   III) introducing a halogenation reagent to the first mixture to        form a second mixture; and

    -   IV) reacting the second mixture.

Embodiment 243. The method of embodiment 242, wherein the acid isselected from sulfuric acid, acetic acid, and combinations thereof.

Embodiment 244. The method of embodiment 243, wherein the acid issulfuric acid.

Embodiment 245. The method of embodiment 242, wherein the halogenationreagent is selected from a chlorination reagent, a bromination reagent,an iodination reagent, and combinations thereof.

Embodiment 246. The method of embodiment 245, wherein the chlorinationreagent is selected from chlorine, thionyl chloride, phosgene,diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorustrichloride, phosphorus oxychloride, trichloroisocyanuric acid, andcombinations thereof.

Embodiment 247. The method of embodiment 246, wherein the chlorinationreagent is trichloroisocyanuric acid.

Embodiment 248. The method of embodiment 242, wherein the method stepIV) of reacting the second mixture occurs at a reaction temperature inthe range of about 10° C. to about 100° C.

Embodiment 249. The method of embodiment 248, wherein the method stepIV) of reacting the second mixture occurs at a reaction temperature inthe range of about 10° C. to about 65° C.

Embodiment 250. The method of embodiment 242, wherein the compound ofFormula II is prepared according to a method comprising

-   -   i) forming a mixture comprising        -   a) a compound of Formula I, wherein

-   -   -   each of R₁-R₅ is independently selected from hydrogen,            halogen, and C₁-C₅ alkyl;        -   b) chloral hydrate;        -   c) a hydroxylamine derivative;        -   d) a solvent;        -   e) an inorganic salt; and        -   f) an acid; and

    -   ii) reacting the mixture.

Embodiment 251. The method of embodiment 250, wherein the hydroxylaminederivative is selected from hydroxylamine sulfate, hydroxylaminehydrochloride, and combinations thereof.

Embodiment 252. The method of embodiment 251, wherein the hydroxylaminederivative is hydroxylamine sulfate.

Embodiment 253. The method of embodiment 250, wherein the solvent isselected from methanol, ethanol, toluene, water, and combinationsthereof.

Embodiment 254. The method of embodiment 253, wherein the solvent iswater.

Embodiment 255. The method of embodiment 250, wherein the inorganic saltis selected from sodium sulfate, sodium hydrogen sulfate, sodiumchloride, sodium disulfite, potassium sulfate, potassium chloride, andcombinations thereof.

Embodiment 256. The method of embodiment 255, wherein the inorganic saltis sodium sulfate.

Embodiment 257. The method of embodiment 250, wherein the acid isselected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromicacid, formic acid, acetic acid, and combinations thereof.

Embodiment 258. The method of embodiment 257, wherein the acid ishydrochloric acid.

Embodiment 259. The method of embodiment 250, wherein the concentrationof the compound of Formula I in the mixture ranges from about 1% toabout 30%.

Embodiment 260. The method of embodiment 259, wherein the concentrationof the compound of Formula I in the mixture is in the range of about 3%to about 10%.

Embodiment 261. The method of embodiment 250, wherein the method step ofreacting the mixture occurs at a reaction temperature in the range ofabout 10° C. to about 100° C.

Embodiment 262. The method of embodiment 261, wherein the method step ofreacting the mixture occurs at a reaction temperature in the range ofabout 50° C. to about 55° C.

In one aspect, a compound of Formula VI is prepared according to amethod represented by Scheme 1. The R groups are as defined anywhere inthis disclosure.

In one aspect, a compound of Formula VI is prepared according to amethod represented by Scheme 2. The R groups are as defined anywhere inthis disclosure.

In one aspect, a compound of Formula VI is prepared according to amethod represented by Scheme 3. The R groups are as defined anywhere inthis disclosure.

In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is preparedaccording to a method represented by Scheme 4.

In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is preparedaccording to a method represented by Scheme 5.

In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is preparedaccording to a method represented by Scheme 6.

In one aspect, a compound of Formula II is prepared according to amethod represented by Scheme 7. The R groups are as defined anywhere inthis disclosure.

This aspect includes reacting a compound of Formula I with chloralhydrate and hydroxylamine sulfate in a solvent at a reactionconcentration in the presence of an inorganic salt and an acid. In oneembodiment, the compound of Formula I is toluidine. In one embodiment,the solvent is selected from MeOH, EtOH, toluene, water, andcombinations thereof. In another embodiment, the solvent is water. Inone embodiment, the inorganic salt is selected from sodium sulfate,sodium hydrogen sulfate, sodium chloride, sodium disulfite, potassiumsulfate, potassium chloride, and combinations thereof. In anotherembodiment, the inorganic salt is sodium sulfate. In one embodiment, theacid is selected from hydrogen chloride, sulfuric acid, nitric acid,hydrobromic acid, formic acid, acetic acid, and combinations thereof. Inanother embodiment, the acid is hydrogen chloride. In one embodiment,the reaction concentration is in the range from about 1% to about 30%for the compound of Formula I. In another embodiment, the reactionconcentration is in the range from about 3% to about 10% for thecompound of Formula I. In one embodiment, the reaction temperature is inthe range from about 10° C. to about 100° C. In another embodiment, thereaction temperature is in the range from about 50° C. to about 55° C.

When reaction conditions of a reaction temperature of 90° C. in waterare applied to a compound of Formula I, wherein the compound of FormulaI is toluidine, (E)-2-(hydroxyimino)-N-(o-tolyl)acetamide is obtained asa sticky solid, leading to a difficult and poor separation. Furthermore,swift increases in temperature are caused when adding this crude(E)-2-(hydroxyimino)-N-(o-tolyl)acetamide by portions in subsequentreaction steps. This problem is overcome in the present disclosure bydecreasing the reaction temperature in water from 90° C. to atemperature in the range from about 50 to about 55° C. This change notonly results in pure (E)-2-(hydroxyimino)-N-(o-tolyl)acetamide with goodmorphotype, but also advantageously increases the reactionconcentration. This high reaction concentration decreases waste waterand cost.

In one aspect, a compound of Formula III is prepared according to amethod represented by Scheme 8. The R groups are as defined anywhere inthis disclosure.

This aspect includes reacting a compound of Formula II with an acid thatis also used as a solvent. In one embodiment, the acid is selected fromhydrochloric acid, sulfuric acid, nitric acid, acetic acid, andcombinations thereof. In another embodiment, the acid is sulfuric acid.In one embodiment, the reaction temperature is in the range from about10° C. to about 90° C. In another embodiment, the reaction temperatureis in the range from about 60° C. to 65° C.

In one aspect, a compound of Formula IV is prepared according to amethod represented by Scheme 9. The R groups are as defined anywhere inthis disclosure.

This aspect includes reacting a compound of Formula III with ahalogenation reagent in a solvent. In one embodiment, the halogenationreagent is selected from fluorination agents, chlorination agents,bromination agents, iodination agents, and combinations thereof. In oneembodiment, the halogenation reagent is a chlorination reagent selectedfrom chlorine, thionyl chloride, phosgene, diphosgene, triphosgene,oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorusoxychloride, trichloroisocyanuric acid, and combinations thereof. Inanother embodiment, the chlorination reagent is sulfuryl chloride. Inone embodiment, the solvent is selected from acetonitrile (ACN),1,2-dichloroethane (DCE), toluene, chlorobenzene, xylene, acetic acid,acetic anhydride, propionic acid, butyric acid, and combinationsthereof. In another embodiment, the solvent is acetic acid. In oneembodiment, the reaction temperature is in the range from about 20° C.to about 140° C. In another embodiment, the reaction temperature is inthe range from about 120° C. to about 130° C.

In one aspect, a compound of Formula IV is prepared according to amethod represented by Scheme 10. The R groups are as defined anywhere inthis disclosure.

This aspect includes reacting, in a first reaction, a compound ofFormula II with an acid that is also used as a solvent, followed byadding a halogenation agent and, in a second reaction, forming acompound of Formula IV. In one embodiment, the acid is selected fromacetic acid, sulfuric acid, and combinations thereof. In anotherembodiment, the acid is sulfuric acid. In one embodiment, thehalogenation reagent is selected from fluorination agents, chlorinationagents, bromination agents, iodination agents, and combinations thereof.In one embodiment, the halogenation reagent is a chlorination reagentselected from chlorine, thionyl chloride, phosgene, diphosgene,triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride,phosphorus oxychloride, trichloroisocyanuric acid, and combinationsthereof. In another embodiment, the chlorination reagent istrichloroisocyanuric acid. In one embodiment, the reaction temperatureof the first reaction is in the range of about 0° C. to about 100° C. Inanother embodiment, the reaction temperature of the first reaction is inthe range of about 10° C. to about 65° C. In one embodiment, thereaction temperature of the second reaction is in the range from about10° C. to about 100° C.

In another embodiment, the reaction temperature of the second reactionis in the range from about 10° C. to 65° C.

This aspect is a single-pot process and possesses several advantages.First, the need to separate intermediates produced from the compound ofFormula II, such as the compound of Formula III, before subsequentreactions is eliminated. Second, potential losses of intermediatesproduced from the compound of Formula II, such as the compound ofFormula III, are reduced. Third, the total yield is increased. Fourth,the number of reaction steps and workup operations is reduced. Fifth,overall cost is reduced.

In one aspect, a compound of Formula V is prepared according to a methodrepresented by Scheme 11. The R groups are as defined anywhere in thisdisclosure.

This aspect includes adding an oxidation agent to an aqueous solutionthat includes a compound of Formula IV in the presence of catalysis. Inone embodiment, the oxidation agent is selected from oxygen, chlorine,sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid,hydrogen peroxide, peroxyacetic acid, potassium peroxymonosulfate,potassium permanganate, and combinations thereof. In another embodiment,the oxidation agent is hydrogen peroxide. In one embodiment, the solventis selected from acetonitrile (ACN), methanol (MeOH), ethanol (EtOH),isopropyl alcohol (i-PrOH), water (H₂O), dimethylformamide (DMF),dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran(THF), acetic acid, acetic anhydride, propionic acid, butyric acid, andcombinations thereof. In another embodiment, the solvent is acetic acid.In one embodiment, the catalyst is selected from sulfuric acid, hydrogenchloride, nitric acid, and combinations thereof. In another embodiment,the catalyst is sulfuric acid. In one embodiment, the reactiontemperature is in the range from about 20° C. to about 100° C. Inanother embodiment, the reaction temperature is in the range from about60° C. to about 65° C.

In one aspect, a compound of Formula VI is prepared according to amethod represented by Scheme 12. The R groups are as defined anywhere inthis disclosure.

This aspect includes reacting a compound of Formula V with an alkylaminein a solvent. In one embodiment, the alkylamine comprises a functionalgroup selected from branched C₁-C₁₀ alkyl and unbranched C₁-C₁₀ alkyl.In another embodiment, the alkylamine is selected from methylamine,ethylamine, propylamine, isopropylamine, butylamine, t-butylamine, andcombinations thereof. In one embodiment, the solvent is selected fromacetonitrile (ACN), 1,2-dichloroethane (DCE), toluene, chlorobenzene,xylene, methanol (MeOH), ethanol (EtOH), isopropyl alcohol (i-PrOH),ethyl acetate (EtOAc), isopropyl acetate (IPAc), and combinationsthereof. In another embodiment, the solvent is EtOAc. In one embodiment,the reaction temperature is in the range from about 0° C. to about 100°C. In another embodiment, the reaction temperature is in the range fromabout 20° C. to about 30° C.

In one aspect, a compound of Formula V is prepared according to a methodrepresented by Scheme 13. The R groups are as defined anywhere in thisdisclosure.

This aspect includes reacting a compound of Formula III with ahalogenation reagent in a solvent, followed by adding an oxidation agentto the solution in the presence of a catalyst. In one embodiment, thehalogenation reagent is selected from fluorination agents, chlorinationagents, bromination agents, iodination agents, and combinations thereof.In another embodiment, the halogenation reagent is a chlorination agentselected from chlorine, thionyl chloride, phosgene, diphosgene,triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride,phosphorus oxychloride, trichloroisocyanuric acid, and combinationsthereof. In another embodiment, the halogenation reagent is sulfurylchloride. In one embodiment, the solvent is selected from ACN, DCE,toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionicacid and butyric acid. In another embodiment, the solvent is aceticacid. In one embodiment, the reaction temperature for the halogenationis in the range from about 20° C. to about 140° C. In anotherembodiment, the reaction temperature for halogenation is in the rangefrom about 120° C. to about 130° C. In one embodiment, the oxidationagent is selected from oxygen, chlorine, sodium hypochlorite, chromiumtrioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, peroxyaceticacid, potassium peroxymonosulfate, potassium permanganate, andcombinations thereof. In another embodiment, the oxidation agent ishydrogen peroxide. In one embodiment, the catalyst is selected fromsulfuric acid, hydrogen chloride, nitric acid, potassium hydroxide, andcombinations thereof. In another embodiment, the catalyst is sulfuricacid. In one embodiment, the reaction temperature for oxidation is inthe range from about 20° C. to about 100° C. In another embodiment, thereaction temperature for oxidation is in the range from about 60° C. toabout 65° C.

This aspect is a single-pot process and possesses several advantages.First, the need to separate intermediates produced from the compound ofFormula III, such as the compound of Formula IV, before subsequentreactions is eliminated. Second, potential losses of intermediatesproduced from the compound of Formula III, such as the compound ofFormula IV, are reduced. Third, the total yield is increased. Fourth,the number of reaction steps and workup operations is reduced. Fifth,overall cost is reduced.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artusing the preceding description can utilize the present invention to itsfullest extent. The following Examples are, therefore, to be construedas merely illustrative, and not limiting of the disclosure in any waywhatsoever. The starting material for the following Examples may nothave necessarily been prepared by a particular preparative run whoseprocedure is described in other Examples. It also is understood that anynumerical range recited herein includes all values from the lower valueto the upper value. For example, if a range is stated as 10-50, it isintended that values such as 12-30, 20-40, or 30-50, etc., are expresslyenumerated in this specification. These are only examples of what isspecifically intended, and all possible combinations of numerical valuesbetween and including the lowest value and the highest value enumeratedare to be considered to be expressly stated in this application.

Example 1. Reaction of o-Toluidine

11.5 g of o-toluidine, 12.0 g of hydrochloric acid, 19.7 g of chloralhydrate, 27.0 g of hydroxylamine sulfate, 30.0 g of sodium sulfate, and200.0 g of water were charged to a reactor. The reaction temperature wascontrolled at 55-60° C. After reaction, the mixture was cooled to roomtemperature and filtrated. The filter cake was washed with water anddried. 13.2 g of high purity of (E)-3-hydroxy-N-(o-tolyl)acrylamide wasobtained.

Example 2. Cyclization

20.0 g of (E)-3-hydroxy-N-(o-tolyl)acrylamide was charged by portions,to control the reaction temperature, to sulfuric acid in a reactor. Thereaction temperature was controlled between 60° C. and 65° C. Afterreaction, the mixture was cooled to room temperature and added to icewater. The mixture was stirred and filtrated. The filter cake was washedwith water and dried. 16.0 g of 7-methylindoline-2,3-dione was obtained.This crude product could be used for subsequent reactions withoutadditional processing.

Example 3. Halogenation

30.0 g of 7-methylindoline-2,3-dione, 50.3 g of sulfuryl chloride, and100.0 g of acetic acid were charged to a reactor. The reactiontemperature was controlled at 120-125° C. After reaction, the mixturewas cooled to room temperature. Water was charged to the mixture, whichwas stirred at room temperature. The mixture was filtrated. The filtercake was washed by water and dried. 29.1 g of5-chloro-7-methylindoline-2,3-dione was obtained.

Example 4. Oxidation

18.0 g of 5-chloro-7-methylindoline-2,3-dione, 100.0 g of acetic acid,and 1.0 g of sulfuric acid was charged to a reactor. The reactiontemperature was controlled at 60-65° C. At this temperature, 13.0 g of30% hydrogen peroxide solution was added dropwise to control thetemperature between 60-65° C. After reaction, water was charged to themixture, which was stirred at room temperature. The mixture wasfiltrated. The filter cake was washed by water and dried. 14.6 of6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione was obtained.

Example 5. Reaction with Methanamine

10.0 g of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione and100.0 g of ethyl acetate was charged to a reactor. Gaseous methanaminewas bubbled to the reaction at room temperature. After reaction, themixture was extracted by water. The organic phase solvent was removedunder vacuum. 8.5 g of crude product of2-amino-5-chloro-N,3-dimethylbenzamide was obtained.

Example 6. One-Pot Synthesis

30.0 g of 7-methylindoline-2,3-dione, 50.3 g of sulfuryl chloride, and164.0 g of acetic acid was charged to a reactor. The reactiontemperature was controlled at 120-125° C. After consumption of7-methylindoline-2,3-dione, the reaction temperature was cooled to60-65° C. 41.4 g of 30% hydrogen peroxide solution was added dropwise tocontrol the temperature between 60-65° C. After reaction, water wascharged to the mixture, which was stirred at room temperature. Themixture was filtrated. The filter cake was washed by water and dried.27.6 g of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione wasobtained.

This written description uses examples to illustrate the presentdisclosure, including the best mode, and also to enable any personskilled in the art to practice the disclosure, including making andusing any devices or systems and performing any incorporated methods.The patentable scope of the disclosure is defined by the claims, and mayinclude other examples that occur to those skilled in the art. Suchother examples are intended to be within the scope of the claims if theyhave structural elements that do not differ from the literal language ofthe claims, or if they include equivalent structural elements withinsubstantial differences from the literal language of the claims.

What is claimed is:
 1. A method of preparing a compound of Formula VI, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen, halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl; wherein at least one of R₇-R₁₀ is a halogen; and wherein R₁₁ is selected from branched C₁-C₁₀ alkyl and unbranched C₁-C₁₀ alkyl, the method comprising I) forming a mixture comprising A) a compound of Formula V, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen, halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl; wherein at least one of R₇-R₁₀ is a halogen; and wherein the compound of Formula V is prepared according to a method comprising i) forming a first mixture comprising  a) a compound of Formula III, wherein

 each of R₁-R₄ is independently selected from hydrogen, halogen, and C₁-C₅ alkyl;  b) a solvent; and  c) a halogenation reagent; ii) reacting the first mixture; iii) introducing a second mixture to the first mixture to form a third mixture, the second mixture comprising  d) an oxidation agent; and  e) a catalyst; and iv) reacting the third mixture; B) an alkylamine; and C) a solvent; and II) reacting the mixture.
 2. The method of claim 1, wherein the alkylamine comprises a functional group selected from branched C₁-C₁₀ alkyl and unbranched C₁-C₁₀ alkyl.
 3. The method of claim 1, wherein the solvent C) is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof.
 4. The method of claim 1, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 0° C. to about 100° C.
 5. The method of claim 1, wherein the solvent b) is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof.
 6. The method of claim 1, wherein the halogenation reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof.
 7. The method of claim 1, wherein the method step ii) of reacting the first mixture occurs at a reaction temperature in the range of about 20° C. to about 140° C.
 8. The method of claim 1, wherein the oxidation agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, peroxyacetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.
 9. The method of claim 1, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, and combinations thereof.
 10. The method of claim 1, wherein the method step iv) of reacting the third mixture occurs at a reaction temperature in the range of about 20° C. to about 100° C.
 11. The method of claim 1, wherein the compound of Formula III is prepared according to a method comprising I) forming a mixture comprising A) a compound of Formula II, wherein

each of R₁-R₅ is independently selected from hydrogen, halogen, and C₁-C₅ alkyl; and wherein the compound of Formula II is prepared according to a method comprising i) forming a mixture comprising a) a compound of Formula I, wherein

each of R₁-R₅ is independently selected from hydrogen, halogen, and C₁-C₅ alkyl; b) chloral hydrate; c) a hydroxylamine derivative; d) a solvent; e) an inorganic salt; and f) an acid; and ii) reacting the mixture; and B) an acid; and II) reacting the mixture.
 12. A method of preparing a compound of Formula VI, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen, halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl; wherein at least one of R₇-R₁₀ is a halogen; and wherein R₁₁ is selected from branched C₁-C₁₀ alkyl and unbranched C₁-C₁₀ alkyl, the method comprising I) forming a mixture comprising A) a compound of Formula V, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen, halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl; wherein at least one of R₇-R₁₀ is a halogen; and wherein the compound of Formula V is prepared according to a method comprising i) forming a mixture comprising  a) a compound of Formula IV, wherein

 each of R₇-R₁₀ is independently selected from hydrogen, halogen, halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl; and  wherein at least one of R₇-R₁₀ is a halogen;  b) an oxidation agent;  c) a solvent; and  d) a catalyst; and ii) reacting the mixture; B) an alkylamine; and C) a solvent; and II) reacting the mixture.
 13. The method of claim 12, wherein the alkylamine comprises a functional group selected from branched C₁-C₁₀ alkyl and unbranched C₁-C₁₀ alkyl.
 14. The method of claim 12, wherein the solvent C) is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof.
 15. The method of claim 12, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 0° C. to about 100° C.
 16. The method of claim 12, wherein the oxidation agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, peroxyacetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.
 17. The method of claim 12, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, and combinations thereof.
 18. A method of preparing a compound of Formula IV, wherein

each of R₇-R₁₀ is independently selected from hydrogen, halogen, halogenated C₁-C₅ alkyl, and C₁-C₅ alkyl; wherein at least one of R₇-R₁₀ is a halogen, the method comprising I) forming a mixture comprising A) a compound of Formula III, wherein

each of R₁-R₄ is independently selected from hydrogen, halogen, and C₁-C₅ alkyl; B) a solvent; C) a halogenation reagent; and II) reacting the mixture.
 19. The method of claim 18, wherein the solvent is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof.
 20. The method of claim 18, wherein R₁ is C₁-C₅ alkyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is hydrogen; R₇ is C₁-C₅ alkyl; R₈ is hydrogen; R₉ is halogen; and R₁₀ is hydrogen. 